Osteitis Fibrosa Cystica

Osteitis fibrosa cystica is the florid skeletal lesion of prolonged, severe hyperparathyroidism. Excess parathyroid hormone drives osteoclastic resorption of cortical and trabecular bone, with replacement of marrow by fibrous tissue and, in advanced disease, cyst like lytic lesions containing haemosiderin and giant cells (brown tumours).

In chronic kidney disease it is the histological expression of high turnover renal osteodystrophy in untreated or refractory secondary and tertiary hyperparathyroidism. It was once common in dialysis patients and is now found mainly in poorly controlled disease, late referral and parathyroid hormone values more than 9 times the upper limit of normal.

Pathophysiology. Sustained parathyroid hormone excess increases osteoclast number and activity and stimulates osteoblasts, producing woven bone and peritrabecular fibrosis. Bone is mechanically weak, with a high fracture risk, and mineral is mobilised into the circulation, worsening hypercalcaemia and soft tissue calcification.

• Bone pain (back, hips, ribs, knees), worse on weight bearing; proximal muscle weakness; waddling gait; difficulty climbing stairs.
• Fractures with minimal trauma (ribs, vertebrae, femoral neck), vertebral collapse with height loss and kyphosis, spontaneous tendon rupture.
• Brown tumours: painless or painful swellings of the jaw, ribs, pelvis, long bones and clavicle; may cause pathological fracture or cord compression.
• Epiphyseal slippage, growth failure and deformity in children.
• Related features: pruritus, red eyes, periarticular and vascular calcification, anaemia with poor response to erythropoietin, hypercalcaemia (polyuria, constipation, confusion).

Red flags

• Parathyroid hormone more than 85 pmol/L (800 pg/mL).
• Pathological fracture, spinal cord compression symptoms or an expanding jaw or skull lesion.
• Corrected calcium above 2.85 mmol/L.
• Painful skin necrosis (calciphylaxis).

Biochemistry

• Intact parathyroid hormone (typically more than 9 times the upper limit of normal), total or bone specific alkaline phosphatase (raised, often above 120 IU/L), corrected calcium (low, normal or high), phosphate (usually high), 25-hydroxyvitamin D, bicarbonate, magnesium, aluminium level in dialysis patients.

Radiology

• Subperiosteal resorption on the radial side of the middle phalanges (earliest and most specific), tufting and acro osteolysis of the terminal phalanges, loss of the lamina dura, resorption of the distal clavicle and pubic symphysis.
• Salt-and-pepper skull, rugger jersey spine, bone cysts and brown tumours as well defined lytic lesions, osteosclerosis, pseudofractures.
• DXA of the distal one third radius shows cortical loss; spine density may be falsely high.
• Isotope bone scan shows a super scan pattern; sestamibi scan with SPECT-CT and ultrasound localise parathyroid tissue before surgery.

Biopsy. Iliac crest biopsy after tetracycline labelling confirms increased osteoclast and osteoblast numbers, peritrabecular fibrosis and increased bone formation rate. Needed when features are mixed or when aluminium toxicity is possible.

Differential diagnosis

• Paget disease (raised alkaline phosphatase, bone expansion, normal parathyroid hormone).
• Multiple myeloma and bone metastases (monoclonal band, free light chains, other primary).
• Giant cell tumour of bone, fibrous dysplasia, osteomalacia (Looser zones, low phosphate), primary hyperparathyroidism, hypophosphatasia.

First line: stop the stimulus

• Phosphate control: dietary phosphorus 800 to 1000 mg daily, sevelamer carbonate 800 mg three times daily with meals titrated to phosphate 1.1 to 1.7 mmol/L; calcium carbonate 500 mg elemental calcium with meals, limiting total elemental calcium from binders to 1.5 g daily.
• Cholecalciferol 50 000 units weekly for 6 to 8 weeks when 25-hydroxyvitamin D is under 25 nmol/L, then 800 to 2000 units daily.
• Dialysis intensification, dialysate calcium 1.25 to 1.5 mmol/L, bicarbonate at least 22 mmol/L.

Lowering parathyroid hormone

• Cinacalcet 30 mg daily with food when calcium is above 2.2 mmol/L, increased every 2 to 4 weeks to a maximum of 180 mg daily; etelcalcetide 5 mg intravenously after each haemodialysis, increased by 2.5 to 5 mg every 4 weeks to a maximum of 15 mg.
• Alfacalcidol 0.25 to 0.5 microg daily or calcitriol 0.25 microg daily, provided calcium is under 2.6 mmol/L and phosphate is under 1.7 mmol/L; paricalcitol 1 microg daily.
• Check calcium within 1 week of each dose change.

Surgery

• Parathyroidectomy when parathyroid hormone stays above 85 pmol/L (800 pg/mL) with hypercalcaemia, hyperphosphataemia, symptomatic bone disease, fractures or brown tumours despite 3 to 6 months of maximal medical therapy. Subtotal (3.5 gland) or total parathyroidectomy with autotransplantation. Brown tumours regress in months after surgery and do not need excision unless they cause fracture or cord compression.
• Hungry bone prevention: alfacalcidol 1 microg daily and calcium carbonate before surgery. After surgery, check calcium every 6 hours for 48 hours; give calcium gluconate 10% 10 mL intravenously over 10 minutes for symptoms or calcium under 1.9 mmol/L, then an infusion of calcium gluconate 10% 100 mL in 1 litre of 5% glucose at 50 mL/hour titrated to calcium 2.0 to 2.2 mmol/L; oral calcium to 2 to 4 g elemental calcium daily, alfacalcidol 1 to 3 microg daily, and replace magnesium.

Symptom relief and fractures

• Paracetamol 1 g four times daily (maximum 4 g daily; 3 g if weight is under 50 kg); avoid NSAIDs. For severe pain, low dose oxycodone 2.5 mg every 6 hours or fentanyl patch 12 microg/hour with renal dose caution; avoid morphine and codeine because of metabolite accumulation.
• Orthopaedic fixation for pathological fractures; spinal decompression for cord compression.
• Bisphosphonates are avoided in high turnover renal osteodystrophy until parathyroid hormone is controlled.

Referral and escalation. Nephrology for any parathyroid hormone more than 9 times the upper limit; endocrine surgery for refractory disease; urgent spinal or orthopaedic review for neurological signs.

Special groups

• Children: alfacalcidol 0.25 to 0.5 microg daily; growth hormone only after parathyroid hormone is controlled.
• Transplant recipients: lesions improve after successful transplantation unless tertiary hyperparathyroidism develops.